Our invention relates to new N-cycloalkylaminoethylbenzamide derivatives and improved pharmacological preparations derived therefrom.
In Fr-1313758 there is described the 4-amino-5-chloro-N-(2-diethylamino)ethyl)-o-anisamide, also known as metoclopramide, which is a drug that has been used for a considerable time in the therapeutic practice as an antiemetic and gastrokinetic drug. Metoclopramide however shows side-effects at the central nervous system level, that can be attributed to a central antidopaminergic activity.
The compounds of the present invention, besides having a stronger gastrokinetic activity compared to metoclopramide, also exhibit a lower central antidopaminergic activity and a lower toxicity, thus showing higher therapeutic indexes. Thus selective activity in the gastrointestinal tract is unexpected and is related to the presence of N-cycloalkyl group.
More specifically, the compounds: 2-methoxy-4-amino-5-chloro-N-(2-(cyclopropylamino)ethyl)-benzamide (Example 1, compound II) and 2-methoxy-4-amino-5-chloro-N-(2-(methylcyclopropylamino)ethyl)-benzamide (Example 2; compound III) show in the rat gastric emptying time test (Brodie D.A. and Kundrats S.K. Proc., 24, 714, 1965) a markedly higher activity than metoclopramide, that is used as a reference drug.
The dosage levels that increase by 50% the gastric transit rate after 3 hours are as follows II= 0.27 (0.20-0.36) mg/kg, III=0.20 (0.08-0.48) mg/kg and metoclopramide =1.67 (0.95-2.93) mg/kg; the compounds II and III are 6.2 and 8.3 times more active than metoclopramide, respectively.
In the central anti-dopaminegeric activity test, by using apomorphine in rat (Janssen P. A. J., Niemegeers C. J. C., Jagenau A. H. M., Arzneim, Forsch., 10, 1003, 1960). metoclopramide exhibits an ED.sub.50 of 2.22 (1.43-3.46) mg/kg versus an ED50 of 4.26 (3.72-4.87) mg/kg for II and of 4.76 (3.39-6.67) mg/kg for III. The compounds II and III are 1.9 and 2.1 times less active than the control drug, respectively.
In the cataleptic activity test (Athee L., Buncombe G. Acta Pharmacol. et toxicol., 35, 429, 1974) metoclopramide exhibits an ED.sub.50 of 43.44 (30.90-61.08) mg/kg versus an ED.sub.50 of&gt;320 mg/kg for II and of 194.66 (164.32-230.54) mg/kg for III. The compounds II and III are more than 10 and 4.5 times less active on the C.N.S. than metoclopramide respectively.
It is evident that the compounds of the present invention have an increased activity on gastric motility and a markedly lower central anti-dopaminergic activity compared with metoclopramide. Based on these data, the compounds of the invention should have markedly reduced side-effects compared with metoclopramide, such as for example the increase of plasma prolactin levels and extrapyramidal reactions in man.
The compounds of the present invention have a low toxicity, for example the LD50 per os in mouse is about 600 mg/kg as of II, about 1600 mg/kg as of III, that of metoclopramide being of about 350 mg/kg.
The present invention also refers to all the industrial aspects relevant to the use of the compounds of the formula I for the treatment of gastritis, dyspeptic-enterocolitic syndromes, as adjuvants in gastric and duodenal ulcers, biliary diskinesia, gastric troubles caused by drugs, digestion-related headache, headache and digestion-related troubles during the menstrual period and pregnancy, psychosomatic disturbances in anxious subjects, in nausea and vomiting related to slow gastric emptying.